Uric Acid Crystals Cause Inflammation
The pain and swelling of gout are caused by uric acid crystals that form in the joint. Uric acid is a waste product of purine metabolism. Uric acid is dissolved in the blood and is excreted through the kidneys into the urine. In people with gout, the uric acid level increases and uric acid crystals are deposited in joints and other tissues. These needle-shaped crystals trigger an immune response that produces intense local inflammation with severe pain, tenderness and swelling. After several years of increased serum uric acid, uric acid crystals can build up in the joint(s) and surrounding tissues. They form deposits that are sometimes apparent as firm lumps (tophi) under the skin. Tophi often are found in or near severely affected joints, on or near the elbow, over the fingers and toes, and in the outer edge of the ear. Uric acid crystals can also form stones in the kidneys, in the ureters and in the bladder. Stones form when the uric acid concentration in the urine is too high - this is cause by low water intake, diuretics, and overly acidic urine. A diet rich in purines may be the culprit.
Uric Acid Production
Uric acid substance is a product of the chemical breakdown of the purine bases that compose the genetic material, DNA and RNA. As cells die and release DNA from their chromosomes, purines are converted into uric acid which is excreted in the urine and, to a lesser extent, the intestinal tract. The concentration of uric acid in the blood is related to the balance between uric acid production and excretion. The normal level in children is about 2 mg/dl. At puberty, the level increases in males by 1 mg/dl, but it does not increase in females; the normal range is 3 to 7 mg/dl in adult males and 2 to 6 mg/dl in adult females. At concentrations greater than 6.5 to 7.0 mg/dl in water, urate precipitates in the form of sodium urate crystals. When blood levels are above 10 mg/dl, the chance of an acute attack of gout is greater than 90 percent.
Only 10% of people with hyperuricemia are over-producers of uric acid caused by diseases of the blood and bone marrow, inherited enzyme abnormalities and metabolic alterations due to obesity. In patients who overproduce uric acid because of a deficiency of hypoxanthine-guanine phosphoribosyltransferase, gout attacks may begin before puberty.
Increased destruction of body cells leads to increased uric acid production; examples are malignancies, particularly lymphoreticular cancers, hemolytic anemia, polycythemia, leukemias and nonmalignant conditions of increased cellular proliferation (e.g., psoriasis). Uric acid production will also increase with the accelerated breakdown of adenosine triphosphate (ATP) in glucose-6-phosphatase deficiency, tissue ischemia and myophosphorylase deficiency.
Decreased urinary excretion of urate most often contributes to hyperuricemia. Patients with urate clearances of 6 to 7 ml per minute are more likely to have hyperuricemia after a purine load than those with clearances of 12 to 14 ml per minute. The assessment of renal handling of urate may be part of medical investigation designed to provide information about urate production, renal function, urine flow and the contribution of dietary purine intake to serum and urine urate.
Gout medications are used to:
Colchicinehas been used to treat gout for over 2,400 years. It relieves the pain and swelling of acute attacks. It works best if taken immediately after the onset of an attack. When taken by mouth, colchicine can cause diarrhea, nausea, and abdominal cramps. Colchicine is less popular now than in the past because of its slow onset of action and frequent gastrointestinal side effects. Colchicine interferes with neutrophil phagocytosis and chemotaxis -early events in the production of joint inflammation and is most effective when started soon after the onset of an attack of gouty arthritis. The beneficial effect of colchicine declines the longer treatment is delayed.
Steroid DrugsMy drug of choice is dexamethasome 4 mg with the onset of gout symptoms. Sometimes a half tablet (2mg) is enough to stop an attack if it is taken as soon as pain and/or swelling becomes apparent. Dexamethasone will increase blood glucose so if you are diabetic on insulin a temporary increase in the insulin dose is usually required.
Nonsteroidal anti-inflammatory drugs
(NSAIDs) are used to relieve the pain and swelling of an acute attack. They usually begin working within 24 hours. These medications are as effective as colchicine but may have less frequent side effects. Side effects from NSAIDs may include stomach upset, headache, skin rashes, and sometimes ulcers.
Medications that Reduce the Rate of Uric Acid Production
Allopurinol (Lopurin, Zurinol, Zyloprim) reduces the amount of uric acid in the blood and urine by slowing the rate of production of uric acid. It is the best medicine for people who have kidney problems or kidney stones caused by uric acid. Occasional side effects include skin rash and stomach upset. Infrequently, allopurinol can cause an allergic reaction - skin rash, hives, itching, fever, nausea, and muscle pain are typical symptoms.
Medications that Help Eliminate Uric Acid
Some drugs lower the uric acid level by increasing the amount of uric acid passed in the urine. They help dissolve tophi and prevent uric acid deposits in joints. Probenecid (Benemid, Parbenem, Probalan) and sulfinpyrazone (Anturane). Common side effects include nausea, skin rash, stomach upset, or headaches. Increase water intake to about 10 x 8 ounce glasses per day.
Avoid aspirin with these drugs because it blocks their effects on the kidneys. At first, probenecid or sulfinpyrazone may increase the risk of kidney stones by increasing the uric acid content in the urine. Adding baking soda to the water will make the urine more alkaline, increase the solubility of uric acid and help to reduce the risk of urinary tract stones. Probenecid, sulfinpyrazone, and allopurinol also may cause more frequent gout attacks at first. You may have to take colchicine or an NSAID for the first few months of preventive drug therapy to prevent a gout attack.
Some drugs lower the uric acid level by increasing the amount of uric acid passed in the urine. They help dissolve tophi and prevent uric acid deposits in joints. Probenecid (Benemid, Parbenem, Probalan) and sulfinpyrazone (Anturane). Common side effects include nausea, skin rash, stomach upset, or headaches. Increase water intake to about 10 x 8 ounce glasses per day. Avoid aspirin with these drugs because it blocks their effects on the kidneys. At first, probenecid or sulfinpyrazone may increase the risk of kidney stones by increasing the uric acid content in the urine. Maintenance of a large volume of alkaline urine increases the solubility of uric acid and thus reduces the risk of stone formation in the kidneys.
Adding baking soda to the water will make the urine more alkaline, increasing the solubility of uric acid, improving excretion and helping to reduce the risk of urinary tract stones.
Probenecid is indicated in patients with disabling attacks of gout. When uric acid concentrations exceed 9 mg/dL increased joint changes and renal complications are likely and treatment should begin even in the absence of gout attacks. The goal of probenecid therapy is to lower serum urate concentrations to about 6 mg/dL. By decreasing serum urate concentrations, probenecid prevents or reduces chronic joint changes and tophi formation, eventually reduces the frequency of acute gout attacks, and may improve renal function in gouty patients.
Since probenecid has no analgesic or anti-inflammatory activity, it is of no value in the treatment of acute gout attacks and will exacerbate and prolong inflammation during the acute phase. Probenecid should not be started until 2—3 weeks after an acute gout attack. The drug may increase the frequency of acute attacks during the first 6—12 months of therapy, even when normal or subnormal serum urate concentrations have been maintained. Acute attacks usually become less severe and are of briefer duration after several months of probenecid therapy. During these acute attacks, probenecid should be continued without changing dosage.
The drug is not effective renal insufficiency exists, particularly in patients with a creatinine clearance of less than 50 mL/minute. Since uricosuric agents tend to increase urinary uric acid concentrations and the risk of stone formation, they should be avoided; allopurinol is preferred in patients with urinary uric acid excretion of greater than 900 mg/day or with gouty nephropathy, urinary tract stones or obstruction, or azotemia. Patients who are refractory to or cannot tolerate probenecid may respond to allopurinol. The activity of allopurinol and uricosurics is additive and when administered concomitantly, smaller doses of each drug can be used. Combined use of the 2 types of drugs is especially effective in the presence of tophaceous deposits.
Probenecid is well tolerated and has a low incidence of adverse effects. The most frequent adverse effects include headache, anorexia, nausea, and vomiting. Hypersensitivity reactions which may be characterized by dermatitis, pruritus, fever, sweating, hypotension, and anaphylactic reaction occur rarely. Most cases of severe allergic reactions and anaphylaxis have been reported to occur within several hours after administration in patients who had previously received the drug. If a hypersensitivity reaction occurs, the drug should be discontinued.
Allopurinol Reducing Uric Acid Production
Allopurinol (Lopurin, Zurinol, Zyloprim) reduces the amount of uric acid in the blood and urine by slowing the rate of production of uric acid. It is the best medicine for people who have kidney problems or kidney stones caused by uric acid. Occasional side effects include skin rash and stomach upset. Infrequently, allopurinol can cause allergic reactions: skin rash, hives, itching, fever, nausea, and muscle pain are typical symptoms. Allopurinol inhibits xanthine oxidase, the enzyme that catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Oxypurinol, a metabolite of allopurinol, also inhibits xanthine oxidase. By inhibiting xanthine oxidase, allopurinol and its metabolite block conversion of the oxypurines (hypoxanthine and xanthine) to uric acid, thus decreasing serum and urine concentrations of uric acid. The drug differs, therefore, from uricosuric agents which lower serum urate concentrations by promoting urinary excretion of uric acid. Xanthine oxidase concentrations are not altered by long-term administration of the drug. Urinary purine output after treatment with allopurinol consists of uric acid, xanthine, and hypoxanthine, each having independent solubility. Thus, the risk of crystalluria is reduced. Alkalinization of the urine increases the solubility of the purines, further minimizing the risk of crystalluria. Decreased tubular transport of uric acid also results in increased renal reabsorption of calcium and decreased calcium excretion.
Allopurinol also interferes with pyrimidine nucleotide synthesis by inhibiting orotidine 5-phosphate decarboxylase. Orotic acid is excreted in the urine in increased amounts rarely exceeding 10% of the total pyrimidines synthesized by the body. In rats, allopurinol reportedly increases liver storage of iron by inhibiting the ferritin-xanthine oxidase system responsible for mobilization of iron from the liver. Allopurinol may also inhibit hepatic microsomal enzymes. Allopurinol is not cytotoxic and has no effect on transplantable tumors. The drug has no analgesic, anti-inflammatory, or uricosuric activity.
The dose of allopurinol varies with the severity of the disease and should be adjusted according to the response and tolerance of the patient. To reduce the possibility of flare-up of acute gouty attacks, the manufacturers recommend that patients be started on allopurinol dosages of 100 mg daily and that the daily dose of the drug be increased by 100 mg at weekly intervals until the serum urate concentration falls to 6 mg/dL or less, or until the maximum recommended dosage of 800 mg daily is reached.In the management of mild gout, the usual adult dosage may range from 200—300 mg daily and, for moderately severe tophaceous gout, from 400—600 mg daily. Serum urate concentrations are often reduced more slowly with allopurinol than with uricosuric drugs and minimum concentrations may not be reached for 1—3 weeks.After serum urate concentrations are controlled, it may be possible to reduce dosage; the average adult maintenance dosage is 300 mg daily and the minimum effective dosage is 100—200 mg daily. Allopurinol therapy should be continued indefinitely; irregular dosage schedules may lead to increased serum urate concentrations.
The most common adverse effect of allopurinol is an itchy maculopapular rash. Dermatitides of the exfoliative, urticarial, erythematous, hemorrhagic, and purpuric types have also occurred. Alopecia, fever, and malaise may also occur alone or in conjunction with dermatitis. In addition, severe furunculoses of the nose, ichthyosis, and Stevens-Johnson syndrome have been reported. The incidence of rash may be increased in patients with renal insufficiency. Skin reactions may be delayed and have been reported to occur as long as 2 years after initiating allopurinol therapy. Rarely, skin rash may be followed by severe hypersensitivity reactions which may sometimes be fatal. Some patients who have developed severe dermatitis have also developed cataracts, but the exact relationship between allopurinol and cataracts has not been established. Pruritus, onycholysis, and lichen planus have also occurred rarely inpatients receiving allopurinol. Facial edema, sweating, and skin edema have also occurred rarely, but a causal relationship to the drug has not been established.
Hypersensitivity reactions to allopurinol have been reported rarely. These reactions are characterized by fever, chills, leukopenia or leukocytosis, eosinophilia, arthralgia, rash, pruritus, nausea, and vomiting. Serious and fatal cases of toxic epidermal necrolysis, hypersensitivity angiitis, and allergic vasculitis involving erythematous maculopapular rash with desquamation, severe exfoliative dermatitis, arterial nephrosclerosis, oliguria, congestive heart failure, and acute onset of permanent deafness have also been reported during therapy with the drug.
Allopurinol-induced hepatotoxicity may also be a hypersensitivity reaction to the drug. A generalized hypersensitivity vasculitis has rarely led to irreversible hepatotoxicity and death. The frequency of allopurinol-induced hypersensitivity reactions may be increased in patients with decreased renal function who receive allopurinol and a thiazide diuretic concomitantly. Allopurinol should usually not be administered to patients who have previously shown hypersensitivity to it or who have had a serious reaction to the drug.
Here is an edited version of allopurinol's drug profile available from Medscape Drug Info online:
“Allopurinol is used to lower serum and urinary uric acid concentrations in the management of primary and secondary gout. The drug is indicated in patients with frequent disabling attacks of gout. Because therapy with allopurinol is not without risks, the drug is not recommended for the management of asymptomatic hyperuricemia. Some clinicians have suggested that therapy should be initiated when serum urate concentrations exceed 9 mg/dL because these concentrations are often associated with increased joint changes and renal complications. Allopurinol is used for the management of gout when uricosurics cannot be used because of adverse effects, allergy, or inadequate response; when there are visible tophi or radiographic evidence of uric acid deposits and stones; or when serum urate concentrations are greater than 9 mg/dL and a family history of tophi and low urate excretion exists. Allopurinol is also used for the management of primary or secondary gouty nephropathy. The goal of therapy is to lower serum urate concentration to about 6 mg/dL. Allopurinol will often promote resolution of tophi and uric acid crystals by decreasing serum urate concentrations. Dosage of allopurinol varies with the severity of the disease and should be adjusted according to the response. To reduce the possibility of flare-up of acute gouty attacks, the manufacturers recommend that patients be started on allopurinol dosages of 100 mg daily and that the daily dose of the drug be increased by 100 mg at weekly intervals until the serum urate concentration falls to 6 mg/dL or less, or until the maximum recommended dosage of 800 mg daily is reached. In the management of mild gout, the usual adult dosage may range from 200—300 mg daily and, for moderately severe tophaceous gout, from 400—600 mg daily. After serum urate concentrations are controlled, it may be possible to reduce dosage; the average adult maintenance dosage is 300 mg daily and the minimum effective dosage is 100—200 mg daily. When allopurinol is added to a therapeutic regimen of colchicine, uricosuric agents, and/or anti-inflammatory agents, a transition period of several months may be necessary before the other drugs can be discontinued. During this period, the drugs should be administered concomitantly, and allopurinol dosage should be adjusted until serum urate concentrations are normal and freedom from acute gouty attacks is maintained for several months. When the uricosuric agent is being withdrawn, dosage of the uricosuric agent should be gradually reduced over several weeks.
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